α-Mangostin

By strategically combining the acylhydrazone scaffold with α-mangostin (α-MG)'s membrane-targeting properties, we designed 48 novel conjugates to enhance antibacterial potential and biofilm penetration while reducing toxicity. The candidate compound 7-8 demonstrated exceptional anti-Methicillin-Resistant Staphylococcus aureus (MRSA) activity (MIC = 1 μg/mL) with in vivo efficacy (5 mg/kg, s.c.) comparable to vancomycin. 7-8 exhibited superior safety profiles versus α-MG, including minimal cytotoxicity (IC₅₀ > 100 μg/mL in A549/LO-2 cells), negligible hemolysis (HC₅₀ > 400 μg/mL), excellent in vivo tolerance, and no genotoxicity. Mechanistic studies revealed a dual antibacterial action: i) membrane disruption causing cellular content leakage, and ii) ROS-mediated oxidative stress. 7-8 also showed remarkable biofilm inhibition/eradication capacity through downregulation of key biofilm genes (ica, agr). Pharmacokinetic evaluation revealed favorable metabolic stability, moderate plasma protein binding, and optimal lipophilicity. These results established 7-8 as a promising multi-target therapeutic candidate against drug-resistant infections, combining enhanced biofilm penetration with improved safety.

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by immune-mediated destruction of liver cells, leading to elevated transaminases, hypergammaglobulinemia, and the presence of autoantibodies. Conventional treatments for AIH, such as corticosteroids and immunosuppressants, are effective but often associated with significant side effects, making the exploration of alternative therapies essential. Natural products, derived from plants and other natural sources, have demonstrated significant hepatoprotective potential in experimental models of AIH, particularly Concanavalin A (Con A)-induced hepatitis, a widely used model for studying the pathogenesis of autoimmune liver injury. This review explores the therapeutic potential and mechanisms of action of various natural products, including betulin, demethyleneberberine, berberine, rosmarinic acid, cucurbitacin E glucoside, pristimerin, α-mangostin, and alpha-lipoic acid. These compounds exert their protective effects through several key pathways, including the NF-κB, AMPK, Nrf2/HO-1, and SIRT1 signaling pathways, which regulate inflammation, oxidative stress, and immune responses. By modulating these pathways, natural products help attenuate inflammation, reduce oxidative damage, and prevent immune-mediated liver injury. The review highlights the growing body of evidence supporting the use of natural compounds as potential therapeutic agents in AIH and emphasizes the need for further clinical research to validate their efficacy and safety in humans. The complex mechanisms through which these natural products modulate immune and inflammatory responses offer promising insights into developing safer and more effective treatments for autoimmune liver diseases.